Benzisothiazoline-1,1-dioxide derivatives, compositions and methods

ABSTRACT

Compounds of the formula ##STR1## wherein R 1  is hydrogen, lower alkyl or phenyl, 
     R 2  is hydrogen, chlorine or methoxy, 
     R 3  is hydrogen or methoxy, 
     R 2  and R 3 , together with each other, are methylenedioxy or ethylenedioxy, 
     R 4  and R 5  are each hydrogen or lower alkyl, 
     R 6  is hydrogen or lower alkoxy, 
     R 7  is lower alkoxy, 
     R 6  and R 7 , together with each other, are methylenedioxy or ethylenedioxy, 
     X is carbonyl or sulfonyl, and 
     n is 2 or 3, 
     And non-toxic, pharmacologically acceptable acid addition salts thereof; the compounds as well as the salts are useful for slowing the heart rate.

This invention relates to novel substituted aralkylamines and non-toxicacid addition salts thereof, as well as to methods of preparing thesecompounds.

More particularly, the present invention relates to a novel class ofaralkylamines represented by the formula ##STR2## wherein R₁ ishydrogen, lower alkyl or phenyl,

R₂ is hydrogen, chlorine or methoxy,

R₃ is hydrogen or methoxy,

R₂ and R₃, together with each other are methylenedioxy or ethylenedioxy,

R₄ and R₅ are each hydrogen or lower alkyl,

R₆ is hydrogen or lower alkoxy,

R₇ is lower alkoxy,

R₆ and R₇, together with each other, are methylenedioxy orethylenedioxy,

X is carbonyl or sulfonyl, and

n is 2 or 3,

And non-toxic, pharmacologically acceptable acid addition salts thereof.

The term "lower alkyl," as used herein to define R₁, R₄ and R₅ isintended to designate alkyl of 1 to about 7 carbon atoms, but preferredembodiments thereof are methyl, ethyl, propyl, or isopropyl.

Similarly, the term "lower alkoxy," as used herein to define R₆ and R₇is intended to designate alkoxy of 1 to about 7 carbon atoms, butpreferred embodiments thereof are methoxy, ethoxy, propoxy orisopropoxy.

The compounds embraced by formula I above may be prepared by thefollowing methods:

Method A

By reacting a compound of the formula ##STR3## wherein R₁, R₂, R₃, X andn have the same meanings as in formula I, and

Z is a leaving group, such as chlorine, bromine, iodine,alkylsulfonyloxy or arylsulfonyloxy,

with a phenylethylamine of the formula ##STR4## wherein R₄, R₅, R₆ andR₇ have the same meanings as in formula I.

The reaction is advantageously carried out in the presence of a solvent,such as methanol, ether, tetrahydrofuran, methylformamide,dimethylformamide, dimethylsulfoxide or benzene, and at a temperaturebetween -50° and 250° C., depending on the reactivity of the leavinggroup Z. The presence of an acid binding agent, for example, an alkalimetal alcoholate, an alkali metal hydroxide or a tertiary organic basesuch as triethylamine or pyridine, or of a reaction accelerator, such aspotassium iodide, is of advantage.

Method B

For the preparation of a compound of the formula I, wherein R₁ ishydrogen and X is carbonyl, by reducing a compound of the formula##STR5## wherein R₂, R₃, R₄, R₅, R₆, R₇ and n have the same meanings asin formula I.

The reduction is preferably carried out in the presence of a solvent,such as glacial acetic acid, water or ethanol, and advantageously withnascent hydrogen, generated, for example, by zinc-glacial acetic acid,tin-hydrochloric acid or tin(II)chloride-hydrochloric acid, or withcatalytically activated hydrogen, at temperatures between 0° and 250°C., preferably, however, between 50° and 100° C.

In those instances where the end product of method A or B is a compoundof the formula I wherein R₄ is hydrogen, that compound may, if desired,be subsequently alkylated, for example by reacting it with acorresponding alkyl halide or dialkyl sulfate; or it may be methylatedby reaction with formaldehyde/formic acid.

The compounds embraced by formula I are organic bases and therefore formaddition salts with inorganic or organic acids. Examples of non-toxic,pharmacologically acceptable acid addition salts are those formed withhydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid,lactic acid, tartaric acid, maleic acid, 8-chlorotheophylline or thelike.

The starting compounds of the formulas II, III and IV are either knowncompounds or may be prepared by known methods.

The following examples illustrate the present invention and will enableothers skilled in the art to understand it more completely. It should beunderstood, however, that the invention is not limited solely to theparticular examples given below.

EXAMPLE 12N-(3-[α-(3,4-Dimethoxy)-phenylethyl-methylamino]propyl)-phthalimidinehydrochloride by method B.

a. 5.04 gm (0.02 mol) of1-[2-(3,4-dimethoxy-phenethyl)-methyl-amino]-3-amino-propane and 2.06 gm(0.02 mol) of phthalic acid anhydride were dissolved in 100 ml ofglacial acetic acid, and the solution was refluxed for 4 hours.Subsequently, the reaction mixture was evaporated in vacuo, the residuewas taken up in chloroform, and the chloroform solution was successivelywashed with a saturated aqueous sodium bicarbonate solution and water.After drying over sodium sulfate, the solvent was distilled off, leaving6.1 gm (79.8% of theory) of amorphous2N-(3-[α-(3,4-Dimethoxy)-phenethylmethylamino]-propyl)-phthalimide,R_(f) -value: 0.4 (benzene/acetone = 1/1).

b. A solution of 6.1 gm (159 millimols) of2N-(3-[α-(3,4-dimethoxy-phenethyl)-methylamino]-propyl)-phthalimide in80 ml of glacial acetic acid was admixed with 10 g of zinc dust, and themixture was refluxed for three hours. Thereafter, the reaction mixturewas filtered while still hot to separate the residual zinc dust, and thefiltrate was evaporated in vacuo. The residue was dissolved inchloroform, and the resulting solution was extracted with a saturatedaqueous bicarbonate solution and then with water, dried over sodiumsulfate and evaporated. The residue was purified by chromatography onsilicagel (chloroform/methanol=19/1), precipitated from etherealhydrochloric acid and digested with ethyl acetate, yielding 2.25 gm (35%of theory) of the hydrochloride of the formula ##STR6## which had amelting point of 146°-148° C.

EXAMPLE 2

a.5,6-Dimethoxy-2N-(3-[α-(3,4-dimethoxy-phenethyl)-methylamino]-propyl)-phthalimidewas prepared analogous to Example 1(a) by condensation of4,5-dimethoxy-phthalic acid anhydride with1-[2-(3,4-dimethoxy-phenyl)-ethyl-methylamino]-3-amino-propane inglacial acetic acid. M.p.: 91°-93° C.

b.5,6-Dimethoxy-2N-(3-[α-(3,4-dimethoxy)-phenylethylmethylamino]-propyl)-phthalimidinehydrochloride was prepared analogous to Example 1(b) by reduction of5,6-dimethoxy-2N-(3-[α-(3,4-dimethoxy-phenethyl)-methylamino]-propyl)-phthalimidewith zinc dust in glacial acetic acid. M.p.: 170°-172° C. EXAMPLE 3

a.5,6-Dimethoxy-2N-(3-[α-(3,4-dimethoxy)-phenylethylamino]-propyl)-phthalimidewas prepared analogous to Example 1(a) by condensation of4,5-dimethoxy-phthalic acid anhydride with1-[2-(3,4-dimethoxy-phenyl)-ethylamino]-3-amino-propane in glacialacetic acid. R_(f) value (chloroform/methanol = 9/1): 0.25.

b.5,6-Dimethoxy-2N-(3-[α-(3,4-dimethoxy)-phenylethylamino]-propyl)-phthalimidinehydrochloride was prepared analogous to example 1(b) by reduction of5,6-dimethoxy-2N-(3-[α-(3,4-dimethoxy)-phenylethylamino]propyl)-phthalimidewith zinc dust in glacial acetic acid. M.p.: 207°-209° C.

EXAMPLE 45,6-Dimethoxy-2N-(3-[α-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidinehydrochloride

5 gm (12.1 mols) of the end product obtained in Example 3(b) were heatedup to 100° C. in a mixture of 1.38 gm (30 millimols) of formic acid and1.5 gm (20 millimols) of formalin for 1 hour. After cooling, thereaction solution was made alkaline by addition of 2 N sodium hydroxide,extracted with chloroform, and the chloroform phase was washed withwater, dried and evaporated in vacuo. The residue was purified bychromatography on silicagel (chloroform/methanol = 45/1), the combinedmain fractions were evaporated, and the base was precipitated as thehydrochloride from ethereal hydrochloric acid. M.p.: 170°-172° C.

EXAMPLE 55,6-Dimethoxy-2N-(3-[α-(3,4-dimethoxy)-phenylethyl-n-propylamino]-propyl)-phthalimidinehydrochloride

A solution of 25 gm (5.5 millimols) of5,6-dimethoxy-2N-(3-[α-(3,4-dimethoxy)-phenylethylamino]-propyl)-phthalimidinein 100 ml of acetone was refluxed for 6 hours after addition of 20 ml of1-bromopropane and 5 gm of potassium carbonate. After cooling, the solidsubstance was filtered off, and the filtrate was evaporated. The residuewas taken up in ether, the insoluble matter was again filtered off, andafter evaporation of the filtrate the hydrochloride was precipitatedfrom ethereal hydrochloric acid. M.p.: 120°-122° C. (acetone/methanol).

EXAMPLE 65,6-Dimethoxy-2N-(3-[α-(3,4-dimethoxy)-phenylethyl-methyl-amino]-ethyl)-phthalimidinehydrochloride by method B

3.81 gm (15 millimols) of N-(2-bromoethyl)-phthalimide were refluxedtogether with 6 gm of 3,4-dimethoxyphenylethyl-N-methylamine in 40 ml ofxylene for 10 hours. The oily residue obtained after evaporation invacuo was converted into the desired compound analogous to Example 1(b)by reduction with zinc dust in glacial acetic acid without furtherpurification. M.p.: 149°-151° C.

EXAMPLE 72N-(3-[α-(3,4-Dimethoxy)-phenylethyl-methylamino]-propyl-3-phenyl-phthalimidineby method A

1.75 gm (5.3 millimols) of N-(3-bromopropyl)-3-phenyl-phthalimidine wererefluxed into 2.06 gm (10.6 millimols) of3,4-dimethoxyphenylethyl-N-methylamine in 30 ml of xylene for 10 hours.After cooling, the mixture was evaporated, and the residue was purifiedby chromotography on silicagel (chloroform/methyl alcohol = 19/1). Thebase was obtained as a highly viscous oil. R_(f) -value(chloroform/methanol = 19/1): 0.4.

EXAMPLE 83-Phenyl-5-chloro-2N-(3-[α-(3,4-dimethoxy)-phenylethyl-methylamino-propyl]-1,2-benzisothiazoline-1,1-dioxidehydrochloride by method A

3 gm (9.3 millimols) ofN-(3-chloropropyl)-3-phenyl-5-chloro-1,2-benzisothiazoline-1,1-dioxidewere refluxed together with 3 gm of3,4-dimethoxy-phenylethyl-N-methylamine and a spatula tipful ofpotassium iodide in a mixture of 30 ml of dimethylformamide and 5 ml oftriethylamine for 5 hours. Subsequently, the reaction mixture wasevaporated to dryness, the residue was taken up in chloroform, and theorganic phase was washed several times with water. After drying, thesolution was evaporated, and the residue was purified by chromatographyon silicagel (chloroform/methanol = 40/1). Precipitation of the purifiedproduct from ethereal hydrochloric acid yielded the amorphoushydrochloride of the formula ##STR7## R_(f) -value (chloroform/methanol= 19/1): 0.5.

C₂₇ H₃₁ ClN₂ O₄ S × HCl (551.54) Calculated: C-58.8%; H-5.60%; N-5.10%;S-5.80% Found: C-58.7%; H-5.75%; N-5.20%; S-5.90%

EXAMPLE 95,6-Dimethoxy-2N-(3-[α-3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-1,2-benzisothiazoline-1,1-dioxidehydrochloride by method A

a. 2-Methyl-4,5-dimethoxy-benzene sulfochloride

23.2 gm (0.2 mol) of chlorosulfonic acid were slowly added dropwise to15.2 gm (0.1 mol) of 3,4-dimethoxy-toluene at about - 10° C., whilestirring and cooling. Afterwards, the mixture was allowed to warm toroom temperature, and was then stirred until the evolution of hydrogenchloride ceased. The reaction mixture was poured over ice, and theprecipitated sulfochloride was extracted with ether. The organic phasewas successively washed with sodium bicarbonate solution and water, andthen evaporated to dryness in vacuo. A turbid oil was obtained as aresidue, which solidified after cooling. R_(f) -value (benzene): 0.5.

b. 2-Methyl-4,5-dimethoxy-benzene sulfonamide

18 gm (0.07 mol) of the compound obtained in step (a) were suspended in200 ml of concentrated ammonia, and the suspension was stirred at roomtemperature for 4 hours. Thereafter, the mixture was suction-filtered,the filter cake was washed with water, and the desired sulfonamide wasobtained as an amorphous product after drying. R_(f) -value(benzene/acetone = 1/1): 0.6.

c. 5,6-Dimethoxy-1,2-benzisothiazoline-3-one-1,1-dioxide

16 gm (0.08 mol) of 2-methyl-4,5-dimethoxy-benzene sulfonamide weredissolved in 500 ml of an aqueous 5% sodium hydroxide solution, and thesolution was heated at its boiling point for 2 hours after addition of39.6 gm (0.25 mol) of potassium permanganate. After cooling, thereaction mixture was suction-filtered through celite, and the desiredproduct was precipitated by addition of concentrated hydrochloric acid.R_(f) -value (benzene/acetone = 3/1): 0.2-0.4.

d. 5,6-Dimethoxy-1,2-benzisothiazoline-1,1-dioxide

7 gm (288 millimols) of the compound obtained in step (c) were refluxedfor 2 hours with 3.3 gm (865 millimols) of lithium aluminum hydride in400 ml of tetrahydrofuran. After cooling, the excess lithium aluminumhydride was decomposed by addition of ethyl acetate, the mixture wasdiluted with water, and subsequently 2 N hydrochloric acid was addeduntil the aluminum hydroxide precipitate was dissolved. The reactionsolution now extracted with ethyl acetate, and the organic phase waswashed with water, dried and evaporated in vacuo. The residue wasdigested in ether, and the desired compound was suction-filtered off.

e. N-(3-Chloropropyl)-5,6-dimethoxy-1,2-benzisothiazoline-1,1-dioxide

2.4 gm (10.5 millimols) of the compound obtained in step (d) weredissolved in a mixture of 15 ml of an aqueous 2.5% sodium hydroxidesolution and 30 ml of ethanol, and the solution was refluxed for 8 hoursafter addition of 10 ml of 3-bromo-1-chloro-propane. The reactionmixture was thereafter evaporated to half its volume, diluted with waterand extracted with chloroform. After drying of the organic phase it wasevaporated in vacuo, and the desired product was obtained as a highlyviscous oil. R_(f) -value (chloroform/methanol = 19/1: 0.8.

f.5,6-Dimethoxy-2N-(3-[α-(3,4-dimethoxy)-phenylethylmethylamino]-propyl)-1,2-benzisothiazoline-1,1-dioxidehydrochloride was prepared analogous to Example 8 by reaction ofN-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisothiazoline-1,1-dioxide with3,4-dimethoxyphenylethyl-N-methylamine. M.p.: 196°-198° C. (acetone).

EXAMPLE 105,6-Methylenedioxy-2N-(3-[α-(3,4-dimethoxy)-phenylethylmethylamino]-propyl)-phthalimidinehydrochloride by method B

a. 3.5 gm (18 millimols of 4,5-methylenedioxy-phthalic acid anhydrideand 4.5 gm (18 millimols) of1-[2-(3,4-dimethoxy-phenyl)-ethylmethylamino]-3-amino-propane wererefluxed in 100 ml of glacial acetic acid for 2 hours. Subsequently, thereaction mixture was evaporated in vacuo, the residue was taken up inchloroform, and the chloroform solution was successively washed with asaturated aqueous sodium bicarbonate solution and water. After dryingover sodium sulfate, the solvent was distilled off, and the desiredsubstance was obtained as an amorphous product. Yield: 4.8 gm (63% oftheory); R_(f) -value (chloroform/methanol = 9/1): 0.6.

b.5,6-Methylenedioxy-2N-(3-[α-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidinehydrochloride

A solution of 4.8 gm (11 millimols) of5,6-methylenedioxy-2N-(3-[α-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidein 40 ml of glacial acetic acid was admixed with 5 gm of zinc dust, andthe mixture was refluxed for 2 hours. Afterwards, the residual zinc dustwas filtered off from the hot reaction solution, and the filtrate wasevaporated in vacuo. The residue was dissolved in chloroform, and theorganic phase was extracted first with a saturated aqueous sodiumcarbonate solution and then with water, dried over sodium sulfate andevaporated. The residue was redissolved in chloroform and the solutionwas admixed with ethereal hydrochloride, yielding 1.5 gm (30% of theory)of the hydrochloride of the formula ##STR8## having a melting point of237°-239° C.

Calculated: C-61.53%; H-6.51%; H-6.24%; Cl-7.90% Found: C-61.50%;H-6.49%; H-6.24%; Cl-7.85%

EXAMPLE 11

a. 4,5-Ethylenedioxy-2N-(3-[α-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimide wasprepared analogous to Example 10(a) by condensation of4,5-ethylenedioxy-phthalic acid anhydride with1-[2-(3,4-dimethoxy-phenyl)-ethylmethylamino]-3-amino-propane in glacialacetic acid. R_(f) value (chloroform/methanol = 9/1): 0.5.

b.5,6-Ethylenedioxy-2N-(3-[α-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine-hydrochloridewas prepared analogous to Example 10(b) by reduction of4,5-ethylenedioxy-2N-(3-[α-(3,4-dimethoxy)-phenylethyl-methylamino]-propylphthalimide with zinc dust in glacial acetic acid. M.p.: 208°-210° C.

Calculated: C-62.26%; H-6.75%; N-6.05%; Cl-7.66% Found: C-62.10%;H-6.84%; N-5.90%; Cl-7.67%

EXAMPLE 12

a.4,5-Methylenedioxy-2N-(3-[α-3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimide

2.7 gm (10 millimols) of4,5-methylenedioxy-N-(3-chloropropyl)-phthalamide and 1.8 gm (10millimols) of 3,4-methylenedioxy-phenylethyl-N-methylamine weredissolved in 20 ml of chlorobenzene, and the solution was refluxed for 8hours after addition of 2.8 gm (20 millimols) of pulverized potassiumcarbonate. Subsequently, the reaction solution was filtered, and thefiltrate was evaporated to dryness in vacuo. The residue was purified bychromatography on silicagel (chloroform/methanol = 19/1), and afterevaporation of the main fraction 2.1 gm (51% of theory) of the desiredcompound were obtained. R_(f) -value (chloroform/methanol = 9/1): 0.6.

b.5,6-Methylenedioxy-2N-(3-[α-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidinehydrochloride was prepared analogous to Example 10(b) by reduction of4,5-methylenedioxy-2N-(3-[α-(3,4-methylenedioxy)-phenylethylmethylamino]-propyl)-phthalimidewith zinc dust in glacial acetic acid. M.p.: 206°-208° C.

Calculated: C-61.04%; H-5.82%; N-6.47%; Cl-8.19% Found: C-61.10%;H-6.07%; N-6.74%; Cl-8.45%

EXAMPLE 13

a.4,5-Ethylenedioxy-2N-(3-[α-(3,4-methylendioxy)-phenylethyl-methylamino]-propyl)-phthalimidewas prepared analogous to Example 12(a) by reaction of4,5-ethylenedioxy-N-(3-chloropropyl)-phthalimide with3,4-methylenedioxy-phenylethyl-N-methylamine in chlorobenzene in thepresence of potassium carbonate. R_(f) -value (chloroform-methanol =9/1): 0.5.

b.5,6-Ethylenedioxy-2N-(3-[α-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl-phthalimidinehydrochloride was prepared analogous to Example 10(b) by reduction of4,5-ethylenedioxy-2N-(3-[α-(3,4-methylenedioxy)-phenylethylmethylamino]-propyl)-phthalimidewith zinc dust in glacial acetic acid. M.p.: 180°-182° C.

Calculated: C-61.81%; H-6.09%; N-6.27%; Cl-7.93% Found: C-61.70%;H-6.12%; N-6.12%; Cl-7.94%

EXAMPLE 14 a.4,5-Dimethoxy-2N-(3-[α-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidewas prepared analogous to Example 12(a) by reaction of 4,5-dimethoxyN-(3-chloropropyl)phthalimide with3,4-methylenedioxy-phenylethyl-N-methylamine in chlorobenzene in thepresence of potassium carbonate. R_(f) -value (chloroform/methanol =19/1): 0.7.

b.5,6-Dimethoxy-2N-(3-[α-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalmidehydrochloride was prepared analogous to Example 10(b) by reduction of4,5-dimethoxy-2N-(3-[α-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)phthalimidewith zinc dust in glacial acetic acid. M.p.: 235°-237° C.

Calculated: C-61.53%; H-6.51%; N-6.24%; Cl-7.90% Found: C-61.45%;H-6.63%; N-6.27%; Cl-7.92%

EXAMPLE 15

5,6-Ethylenedioxy-2-(3-[α-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-1,2-benzisothiazoline-1,1-dioxidehydrochloride was prepared analogous to Example 12(a) by reaction ofN-(3-chloropropyl)-5,6-ethylenedioxy-1,2-benzisothiazoline-1,1-dioxidewith 3,4-dimethoxy-phenylethyl-N-methylamine. R_(f) -value(chloroform/methanol = 9/1): 0.6.

EXAMPLE 163-Methyl-5,6-dimethoxy-2N-(3-[α-(3,4-dimethoxy)-phenylethylmethylamino]-propyl)-phthalimidinehydrochloride was prepared analogous to Example 12(a) by reaction of3-methyl-5,6-dimethoxy-N-(3-chloropropyl)-phthalimidine with3,4-dimethoxyphenylethyl-N-methylamine in chlorobenzene in the presenceof potassium carbonate. M.p.: 135°-136° C.

Calculated: C-62.68%; H-7.36%; N-5.85%; Cl-7.40% Found: C-62.31%;H-7.40%; N-5.80%; Cl-7.12%

EXAMPLE 17

a.4,5-Dimethoxy-2N-(3-[α-(3,4-dimethoxy)-phenylisopropyl-methylamino]-propyl)-phthalimidewas prepared analogous to Example 12(a) by reaction of4,5-dimethoxy-N-(3-chloropropyl)-phthalimide with3,4-dimethoxy-phenyl-isopropyl-N-methylamine in chlorobenzene in thepresence of potassium carbonate. R_(f) -value (chloroform/methanol =9/1): 0.9.

b.5,6-Dimethoxy-2N-(3-[α-(3,4-dimethoxy)-phenylisopropyl-methylamino]-proply)-phthalimidinehydrochloride was prepared analogous to Example 10(b) by reduction of4,5-dimethoxy-2N-(3-[α-(3,4-dimethoxy)-phenylisopropyl-methylamino]-propyl)-phthalimidewith zinc dust in glacial acetic acid. M.p.: 183°-185° C.

Calculated: C-62.68%; H-7.36 %; N-5.85%; Cl-7.40%; Found: C-62.50%;H-7.42%; N-5.92%; Cl-7.30%

EXAMPLE 18

a.4,5-Methylenedioxy-2N-(2-[α-(3,4-dimethoxy)-phenylethyl-methylamino]-ethyl)-phthalimidewas prepared analogous to Example 10(a) from 4,5-methylenedioxy-phthalicacid anhydride and1-[2-(3,4-dimethoxy-phenyl)-ethyl-methylamino]-2-amino-ethane. R_(f)-value (chloroform/methanol = 9:1): 0.55.

b.5,6-Methylenedioxy-2N-(2-[α-(3,4-dimethoxy)-phenylethyl-methylamino]-ethyl)-phthalimidine-hydrochloridewas prepared analogous to Example 10(b) by reduction of4,5-methylenedioxy-2N-(2-[α-(3,4-dimethoxy)-phenylethyl-methylamino]-ethyl)-phthalimide withzinc dust in glacial acetic acid. R_(f) -value (chloroform/methanol =9:1): 0.4.

The compounds embraced by formula I and their non-toxic,pharmacologically acceptable acid addition salts have usefulpharmacodynamic properties. More particularly, they primarilyselectively reduce the heart rate and also exhibit mild hypotensiveactivity in warm-blooded animals, such as guinea pigs.

The heart rate reducing activity and the acute toxicity of the compoundsof this invention were ascertained by the standard pharmacological testmethods described below, and the test results for a few representativecompounds are given, where

A =5,6-Dimethoxy-2N-(3-[α-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidinehydrochloride,

B =5,6-Dimethoxy-2-(3-[α-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-1,2-benzisothiazoline-1,1-dioxidehydrochloride,

C =5,6-Methylenedioxy-2N-(3-[α-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidinehydrochloride,

D =5,6-Dimethoxy-2N-(3-[α-(3,4-methylenedioxy)-phenylethylmethylamino]-propyl)-phthalimidinehydrochloride and

E =5,6-Ethylenedioxy-2N-(3-[α-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidinehydrochloride.

1. Activity on heart frequency of anesthetized guinea pigs:

The heart rate of guinea pigs under urethane anesthesia was registeredby an electrocardiogram. The test compound was administeredintravenously at increasing dosage increments between 0.5 and 20 mg/kg.

The following table shows the results obtained:

                  TABLE I                                                         ______________________________________                                                Dose                                                                          mg/kg                                                                 Compound                                                                              i.v.     n     Percentage change in heart rate                        ______________________________________                                                0.5      3     -23.5                                                          1.0      3     -36.1                                                          2.0      3     -47.2                                                  A       5.0      3     -51.6                                                          10.0     3     -59.1                                                          20.0     3     -67.2                                                          0.5      5     -9.8                                                           1.0      5     -20.0                                                          2.0      5     -27.4                                                  B       5.0      5     -37.6                                                          10.0     5     -46.9                                                          20.0     5     -53.9                                                  ______________________________________                                         n = number of animals per dose                                           

2. Effect on heart rate in the isolated auricle of the guinea pig:

The effect on isolated, spontaneously beating auricles of guinea pigs ofmale and female sex having a body weight between 300 and 400 gm wereinvestigated in an organ bath filled with tyrode solution. The nutritivesolution was infused with carbogen (95% of O₂ and 5% of CO₂) andmaintained at 30° C. The contractions were registered isometrically witha Statham-Force-transducer on a Grass-polygraph. The test compound wasadded to the organ bath so that the final concentration was 10⁻ ⁵ g/mlin each case. 5 auricles were used for each solution.

The following table gives the percentage decrease in the heart rate froman average of 5 auricles at a test compound concentration of 10⁻ ⁵g/ml).

                  TABLE II                                                        ______________________________________                                        Compound       Change in heart rate in %                                      ______________________________________                                        A              -52                                                            B              -60                                                            D              -51                                                            E              -48                                                            ______________________________________                                    

3. Acute toxicity:

The acute toxicity of the compounds in question was determined in mice(observation time: 14 days) after oral or intravenous application. TheLD₅₀ was calculated from the percentage of animals which died afterdifferent doses within the observation time (see J. Pharmacol. exp.Therap. 96, 99 (1949)):

                  TABLE III                                                       ______________________________________                                        Compound         LD.sub.50                                                    ______________________________________                                        A                98       mg/kg i.v.                                          A                1,570    mg/kg p.o.                                          B                100      mg/kg i.v.                                          ______________________________________                                    

For pharmaceutical purposes the compounds of the present invention areadministered to warm-blooded animals perorally, parenterally or rectallyas active ingredients in customary dosage unit compositions, that is,compositions in dosage unit form consisting essentially of an inertpharmaceutical carrier and one effective dosage unit of the activeingredient, such as tablets, coated pills, capsules, wafers, powders,solutions, suspensions, emulsions, syrups, suppositories and the like.One effective heart rate reducing dosage unit of the compounds accordingto the present invention is from 0.33 to 5.0 mgm/kg body weight,preferably from 0.41 to 3.34 mgm/kg body weight.

The following examples illustrate a few pharmaceutical dosage unitcompositions comprising a compound of the present invention as an activeingredient and represent the best modes contemplated of putting theinvention into practical use. The parts are parts by weight unlessotherwise specified.

EXAMPLE 19

Tablets

The tablet composition is compounded from the following ingredients:

    ______________________________________                                        5,6-Dimethoxy-2N-(3-[α-(3,4-dimethoxy)-                                 phenethyl-methylamino]-propyl)-phthal-                                        imidine hydrochloride   100.0    parts                                        Lactose                 50.0     parts                                        Polyvinylpyrrolidone    5.0      parts                                        Carboxymethyl cellulose 19.0     parts                                        Magnesium stearate      1.0      part                                         Total                   175.0    parts                                        ______________________________________                                    

Preparation:

The phthalimidine compound and the lactose are intimately admixed witheach other, the mixture is granulated with the aid of an aqueoussolution of the polyvinylpyrrolidone, the granulate is dried, the drygranulate is admixed with the remaining ingredients, and the resultingcomposition is compressed into 175 mgm-tablets in a conventional tabletmaking machine. Each tablet contains 100 mgm of the phthalimidinecompound and is an oral dosage unit composition with effective heartrate reducing action.

EXAMPLE 20

Coated pills

The pill core composition is compounded from the following ingredients:

    ______________________________________                                        5,6-Methylenedioxy-2N-(3-[α-(3,4-                                       dimethoxy)-phenethyl-methylamino] -                                           propyl)-phthalimidine hydrochloride                                                                    50.0    parts                                        Corn starch, dry         20.0    parts                                        Soluble starch           2.0     parts                                        Carboxymethyl cellulose  7.0     parts                                        Magnesium stearate       1.0     part                                         Total                    80.0    parts                                        ______________________________________                                    

Preparation:

The pill core composition is compounded in analogy to the tabletcomposition in the preceding example, and the composition is compressedinto 80 mgm-pill cores which are subsequently coated with a thin shellconsisting essentially of a mixture of talcum and gum arabic: Eachcoated pill contains 50 mgm of the phthalimidine compound and is an oraldosage unit composition with effective heart rate reducing action.

EXAMPLE 21

Rectal suppositories

The suppository composition is compounded from the followingingredients:

    ______________________________________                                        5,6-Dimethoxy-2-(3-[α-(3,4-dimethoxy)-                                  phenethyl-methylamino]-propyl)-1,2-                                           benzisothiazoline-1,1-dioxide hydro-                                          chloride                150.0    parts                                        Suppository base (e.g. cocoa butter)                                                                  1550.0   parts                                        Total                   1700.0   parts                                        ______________________________________                                    

Preparation:

The suppository base is melted, the benzisothiazoline compound ishomogeneously dispersed therein; and 1700 mgm-portions of the resultingmixture are poured into cooled suppository molds and allowed to hardentherein. Each suppository contains 150 mgm of the benzisothiazolinecompound and is a rectal dosage unit composition with effective heartrate reducing action.

EXAMPLE 22

Suspension

The suspension is compounded from the following ingredients:

    ______________________________________                                        5,6-Ethylenedioxy-2N-(3-[α-(3,4-methylene-                              dioxy)-phenethyl-methylamino]-propyl)-                                        phthalimidine hydrochloride                                                                            5.0  parts                                           Carboxymethyl cellulose  0.1  part                                            Methyl p-hydroxy-benzoate                                                                              0.05 part                                            Propyl p-hydroxy-benzoate                                                                              0.01 part                                            Sugar                    10.0  parts                                          Glycerin                 5.0  parts                                           Sorbitol solution, 70%   20.0  parts                                          Flavoring                0.3  part                                            Distilled water    q.s.ad                                                                              100.0  parts                                                                  by vol.                                              ______________________________________                                    

Preparation:

The distilled water is heated to 70° C., and the p-hydroxybenzoates aswell as the glycerine and the carboxymethyl cellulose are dissolvedtherein. The solution is cooled to room temperature, and thephthalimidine compound is added while stirring. The solution is thenmade homogeneous. After addition of the sugar, the sorbitol solution andthe flavoring, the resulting suspension is evacuated for de-aeration,while stirring.

5 ml of the suspension contain 250 mgm of the phthalimidine compound andare an oral dosage unit composition with effective heart rate reducingaction.

Analogous results are obtained when any one of the other compoundsembraced by formula I or a non-toxic, pharmacologically acceptable acidaddition salt is substituted for the particular active ingredient inExamples 19 through 22. Likewise, the amount of active ingredient inthese illustrative examples may be varied to achieve the dosage unitrange set forth above, and the amounts and nature of the inertpharmaceutical carrier ingredients may be varied to meet particularrequirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to these particularembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim:
 1. A compound of the formula ##STR9## wherein R₁ is hydrogen,lower alkyl or phenyl,R₂ is hydrogen, chlorine or methoxy, R₃ ishydrogen or methoxy R₂ and R₃, together with each other, aremethylenedioxy or ethylenedioxy, R₄ and R₅ are each hydrogen or loweralkyl, R₆ is hydrogen or lower alkoxy, R₇ is lower alkoxy, R₆ and R₇,together with each other, are methylenedioxy or ethylenedioxy, and n is2 or 3,or a non-toxic, pharmacologically acceptable acid addition saltthereof.
 2. A compound of claim 1, which is5,6-dimethoxy-2-(3-[α-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-1,2-benzisothiazoline-1,1-dioxideor a non-toxic, pharmacologically acceptable acid addition salt thereof.3. A pharmaceutical dosage unit composition consisting essentially of aninert pharmaceutical carrier and an effective heart rate reducing amountof a compound of claim
 1. 4. The method of reducing the heart rate in awarm-blooded animal in need of such treatment, which comprisesperorally, parenterally or rectally administering to said animal aneffective heart rate reducing amount of a compound of claim 1.